PROJECT SUMMARY/ABSTRACT Lewy body dementia (LBD) is a term used to encompass both Parkinson?s disease dementia (PDD) and dementia with Lewy body (DLB) disorders. They are the second most common type of dementia after Alzheimer?s disease but are yet often misdiagnosed. Indeed, LBD appears to fall somewhere in the middle of a disease spectrum ranging from Alzheimer?s to Parkinson?s disease. Despite abundant evidence of a central role for alpha-synuclein (?syn) in LBD pathogenesis, evidence shows that tau lesions, such as hyper phosphorylated tau protein, often coexists in DLB and PDD brains. Comorbid ?syn and tau pathology may be critical for the formation of disease-specific pathogenic aggregates that determine susceptibility to developing disease. Post-mortem brain investigations have reported presence of tau oligomers colocalizing with ?syn oligomers and in vitro and in vivo studies demonstrated that ?syn and tau promote the fibrilization of one another. Yet, a major unanswered question in the field is what mechanisms underlie LBD and how ?syn/tau interplay influences neurodegenerative processes. Rodent models continue to play a key role in advancing our understanding of neurodegenerative disorders and are a valuable tool to decipher mechanism of diseases. Development of models recapitulating the comorbid pathology and differential clinical symptom onset of PDD and DLB will help the field to better understand LBD pathogenesis and the cellular mechanisms that lead to neurodegeneration. Herein, we propose to identify the role of in-vivo ?syn/tau crosstalk and help to elucidate how tau and ?syn exert their toxicity in de novo mouse models where temporally controlled co-pathology will be induced. Indeed we will use AAV vector technology to transduce tau or ?syn expression in the adult brain of transgenic animals already presenting or ?syn or tau pathology respectively. Overall, the objective is to identify if ?syn and tau interplay results in enhanced pathology and dysfunction in these two different animal models. To answer these questions behavioral, histological and biochemical analyses will be conducted. These approaches will yield important insight into ?syn/tau interaction in vivo and may have the potential to model PDD and DLB pathology independently.